The present invention relates to compositions and methods for treating sexual dysfunctions in mammalian subjects, particularly human males.
The DSM-IIIR defines four phases of sexual response (appetite, excitement, orgasm, resolution). Inhibition of any of these is collectively known as "sexual dysfunction." Sexual dysfunction in males specifically encompasses the inability to sustain a penile erection (Male Erectile Disorder or impotence), the inability to ejaculate and/or the inability to experience orgasm.
According to the DSM-III-R (p. 292), approximately 8% of young adult males have Male Erectile Disorder. An estimated 20% of the total population have Hypoactive Sexual Desire Disorder.
Male sexual dysfunction may be due to one or more causes.
About forty to sixty percent of cases of Male Erectile Disorder is associated with atherosclerosis of the arteries supplying blood to the penis ("arteriogenic" or "atherosclerotic" dysfunction). In some cases, there is leakage from veins in the penis such that sufficient pressure for an erection can neither be obtained nor maintained.
"Neurogenic" sexual dysfunction associated with a neuropathy (e.g., nerve damage in the nervous system affecting the penis arising from, for example, surgery or a pelvic injury) accounts for about ten to fifteen percent of impotence cases.
Psychological or "psychogenic" dysfunction, resulting, for example, from anxiety or depression, with no apparent substantial somatic or organic impairment, accounts for about fifteen to twenty percent of cases of impotence. These include an age-associated sexual decline which occurs unaccompanied by any overt pathologies.
Erectile insufficiency is sometimes a side effect of certain drugs, such as beta-blockers that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption is a cause of erectile insufficiency. These forms of sexual dysfunction may be regarded as a subset of neurogenic or psychogenic insufficiency.
In most cases, no hormonal or primarily structural (anatomical) defects are clinically demonstrable. This common type of impotence usually increases in frequency with advancing age. About twelve percent of adult men under age forty-five, about twenty percent of men at age sixty, and about fifty-five percent of men at age seventy-five experience difficulty in engaging in sexual intercourse.
A number of methods to treat sexual dysfunction are available. These treatments include surgery (e.g., penile implants), pharmacological treatments and, in cases of psychogenic dysfunction, psychological counseling. See, e.g., U.S. Pat. No. 5,399,581 to Laragh, Mar. 21, U.S. Pat. No. 5,439,007 to Fischer, Aug. 8, 1995, U.S. Pat. No. 5,447,912 to Gerstenberg et al., Sep. 5, 1995, U.S. Pat. No. 5,451,609 to Bellamy, Sep. 19, 1995, and references cited therein.
These published pharmacological methods of treatment have primarily targeted peripheral nervous system responses. They have had only limited success, and there are potentially severe side-effects.
Testosterone has been shown to be effective in modulating sexual behavior in a variety of mammals, including rats and humans. See, e.g., Smith et al. (1992), Hormones and Behaviour 26: 110-135 (rats) and Carani et al. (1990), Arch. Sex. Behav. 19: 223-234 (humans). However, steroid treatments have the potential for eliciting undesirable behaviors, for example, aggression.
Injection of or moxisylyte (ICAVEX) (U.S. Pat. No. 5,451,609 to Bellamy, Sep. 19, 1995), the smooth muscle relaxant papaverine, or the non-specific blocker and hypotensive phenoxybenzamine into a corpus cavernosum has been reported to cause an erection sufficient for vaginal penetration. Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved.
In cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an alpha-adrenergic blocker, causes an erection that suffices for vaginal penetration. The resulting erection is one of significantly shorter duration than that induced by intracavernosal injection of papaverine or phenoxybenzamine. It often is of such short duration that satisfactory sexual relations are difficult or impossible.
The neuropeptide vasoactive intestinal peptide ("VIP") is thought to be associated with erections in normal males (i.e., males not suffering from erectile insufficiency). Injection of VIP into a corpus cavernosum of a normal male without subjecting the male to sexual stimulation causes slight swelling (slight tumescence) of the penis but not an erection. When coupled with visual sexual stimulation or sexual stimulation by vibration or both, injection of small amounts of VIP into a corpus cavernosum of a normal male facilitates full erection (see, Wagner et al. (1987) World J. Urol. 5: 171-172). VIP alone or coupled with sexual stimulation does not induce erections in males whose impotence is due to severe atherosclerosis.
It will be readily apparent that such invasive treatments require of the patient a great sense of purpose and a single-minded dedication to the task at hand, and that they may actually hinder rather than facilitate sexual activity. Intracavernosal injection is often associated with a burning sensation after the injection. In addition, papaverine or phenoxybenzamine can result in priapism, a persistent erection lasting from a few hours to sometimes longer than twenty-four hours. Priapism is a serious side effect of treatment of erectile insufficiency with these drugs. Beyond the embarrassment that some men may experience, priapism is often painful, can irreversibly damage erectile tissue, and, to be relieved, requires bleeding or pharmacological intervention, such as injection of a sympathomimetic drug such as adrenaline. There are indications that repeated use of papaverine causes extensive intracavernous fibrosis.
In summary, although sexual dysfunction is a pervasive problem, there are few satisfactory methods available for treating this disorder. Therefore, it is an object herein to provide methods and compositions for treating sexual dysfunctions.